The present invention relates to the use of a biodegradable polymer scaffold for tissue engineering applications. More particularly, the present invention relates to a novel macroporous polymer scaffold having a high level of interconnectivity between macropores.
Bone treatments for injuries, genetic malformations and diseases often require implantation of grafts. It is well known that autografts and allografts are the safest implants; however, due to the limited supply and the risks of disease transmission and rejection encountered with these grafts, synthetic biomaterials have also been widely used as implants. Complications in vivo were observed with some of these biomaterials, as mechanical mismatches (stress shielding) and appearance of wear debris lead to bone atrophy, osteoporosis or osteolysis around the implants (Woo et al., 1976; Terjesen et al., 1988).
A new approach, defined as Tissue Engineering (TE), has recently raised a lot of interest. Tissue engineering involves the development of a new generation of biomaterials capable of specific interactions with biological tissues to yield functional tissue equivalents. The underlying concept is that cells can be isolated from a patient, expanded in cell culture and seeded onto a scaffold prepared from a specific biomaterial to form a scaffold/biological composite called a xe2x80x9cTE constructxe2x80x9d. The construct can then be grafted into the same patient to function as a replacement tissue. Some such systems are useful for organ tissue replacement where there is a limited availability of donor organs or where, in some cases (e.g. young patients) inadequate natural replacements are available. The scaffold itself may act as a delivery vehicle for biologically active moieties from growth factors, genes and drugs. This revolutionary approach to surgery has extensive applications with benefits to both patient well-being and the advancement of health care systems.
The application of tissue engineering to the growth of bone tissue involves harvesting osteogenic stem cells, seeding them and allowing them to grow to produce a new tissue in vitro. The newly obtained tissue can then be used as an autograft. Biodegradable polyestersxe2x80x94in particular poly(lactide-co-glycolide)sxe2x80x94have been used as scaffolds for tissue engineering of several different cell populations, for example: chondrocytes (as described by Freed et al. in the J. of Biomed. Mater. Res. 27:11-13, 1993), hepatocytes (as described by Mooney et al. in the Journal of Biomedical Mat. Res. 29, 959-965, 1995) and most recently, bone marrow-derived cells (as described by Ishaug et al. in the J. Biomed. Mat. Res. 36: 17-28, 1997 and Holy et al., in Cells and Materials, 7, 223-234, 1997). Specifically, porous structures of these polyesters were prepared and seeded with cells; however, when bone marrow-derived cells were cultured on these porous structures, bone in growth only occurred within the outer edge of 3-D polymeric scaffold (Ishaug et al., supra; Holy et al., supra). Thus, the polymeric scaffolds prepared in these instances were inadequate to allow for the cell growth required to render tissue suitable for implantation or for use as an autograft.
The method of producing polymer scaffolds disclosed in Thomson et al., Fabrication of Biodegradable Polymer Scaffolds to Engineer Trabecular Bonexe2x80x9d, J. Biomater. Sci. Polymer Edn. Vol. 7, No. 1 pp. 23-38, 1995 VSP, involves formation of gelatin beads, after which a polymer is then xe2x80x9cmeltedxe2x80x9d at 80xc2x0 C. and 333 g pressure around the beads after which the bead/polymer composite is cooled down, and the gelatin is leached out in distilled deionized water. The polymer is forming sheets of material around the beads and is in a solid state before the leaching of the beads/particulate.
U.S. Pat. No. 5,338,772 issued to Bauer et al. is directed to an implant material which is a composite of calcium phosphate ceramic particles and a bioadsorbable polymer. In the method of preparation disclosed in Bauer, calcium phosphate powder is mixed with a polymer and the mixture is subjected to microwave energy which melts the polymer to a liquid that forms a polymer coating around the particles with polymer bridges between encased particles.
It has now been found that polymer scaffolds characterized by macropores in the millimeter size range with interconnections as seen in trabecular bone, are particularly useful for tissue engineering as they allow cell in growth which is crucial for the development of three-dimensional tissue. Such polymer scaffolds can be prepared using a novel process which combines the techniques of phase-inversion and particulate-leaching.
Accordingly, in one aspect of the present invention, there is provided a polymer scaffold comprising macropores, ranging in size between 0.5 mm to 3.5 mm, and having an interconnecting porosity similar to that found in human trabecular bone.
The present invention provides a macroporous polymer scaffold comprising microporous polymer struts defining macropores which are interconnected by macroporous passageways, including microporous passageways extending through the microporous polymer struts so that macropores on either side of a given microporous polymer strut are in communication through the given microporous polymer strut, said macropores having a mean diameter in a range from about 0.5 to about 3.5 mm, and the macroporous polymer scaffold having a porosity of at least 50%.
The present invention also provides a macroporous polymer scaffold comprising microporous polymer struts defining macropores which are interconnected by macroporous passageways, including microporous passageways extending through the microporous polymer struts so that macropores on either side of a given microporous polymer strut are in communication through the given microporous polymer strut, the macropores having a mean diameter in a range from about 0.5 to about 3.5 mm, the macroporous passageways connecting macropores having a mean diameter in a range from about 200 xcexcm to about 2 mm, and wherein the microporous passageways have a mean diameter less than about 200 xcexcm, and the macroporous polymer scaffold having a porosity of at least 50%.
In another aspect of the present invention, a process for making a polymer scaffold is provided comprising the steps of
mixing liquid polymer with particles to form a particulate-polymer mixture;
submerging the particulate-polymer mixture in a polymer non-solvent to precipitate said polymer producing a solidified particulate-polymer mixture; and
submerging the solidified particulate-polymer mixture into a particulate solvent for a time sufficient to dissolve the particles.
In another aspect of the invention there is provided a process for growing tissue, with pervasive distribution, in a macroporous polymer scaffold including macropores to a depth of at least 2.5 times an average macropore size in the scaffold, comprising the steps of:
synthesizing a macroporous polymer scaffold with a trabecular morphology having a porosity of at least 50%, including interrupted pore walls and polymer struts defining macropores which have a mean diameter in a range from about 0.5 to about 3.5 mm and are interconnected by macroporous passageways having a size in a range from about 200 xcexcm to about 2 mm;
seeding the polymer scaffold with tissue cells; and
culturing said tissue cells.
In accordance with one embodiment of the invention a macroporous polymer scaffold is disclosed comprising porous walls that are essentially non-membranous. The porous walls consist of microporous polymer struts which define macropores which are interconnected by macroporous passageways. The microporous polymer struts contain microporous passageways extending through the microporous polymer struts so that macropores on either side of a given microporous polymer strut are in communication through the given microporous polymer strut. The macropores have a mean diameter in a range from about 0.5 to about 3.5 mm, and the macroporous polymer scaffold has a porosity of at least 50%.
According to another embodiment of the invention, a macroporous polymer scaffold is disclosed comprising porous walls that are essentially non-membranous. The porous walls consist of microporous polymer struts which define macropores which are interconnected by macroporous passageways. The microporous polymer struts contain microporous passageways which extend through the microporous polymer struts so that macropores on either side of a given microporous polymer strut are in communication through the given microporous polymer strut. the macropores have a mean diameter in a range from about 0.5 to about 3.5 mm. The macroporous passageways connecting macropores have a mean diameter in a range from about 200 xcexcm to about 2 mm, and the microporous passageways have a mean diameter less than about 200 xcexcm. The macroporous polymer scaffold has a porosity of at least 50%.